A tumor-selective prodrug can be selectively converted in vivo into a more active compound and kills locally tumor cell, which can avoid the side-effect on human body resulted from systematic or topically direct administration. Thus, it has a considerably excellent prospect for treating tumors.
Due to disordering of their proliferation, most of malignant tumors always generate a hypoxic region which is resistant to both radiation therapy and chemical medicine therapy, and some time the treatment fails due to further development of the tumors; and since the normal tissues in the human body have abundant oxygen, the hypoxia is chosen as a physiological characteristics targeting to tumors. A hypoxia-activated prodrug makes use of the said physiological characteristics of the tumors, that is, a non-toxic prodrug can be activated into a toxic compound under a hypoxic environment by a particular enzyme, thus attaining an anti-tumor effect.
Therapies in which a non-toxic drug is converted into a toxic drug include “antibody-directed enzyme prodrug therapy (ADEPT)”, “gene-directed enzyme prodrug therapy (GDEPT)”, “virus-directed enzyme prodrug therapy” (VDEPT), or “cell ablation therapy”. Among them, the “antibody-directed enzyme prodrug therapy (ADEPT)” was disclosed in WO88/07379; the “gene-directed enzyme prodrug therapy (GDEPT)” was disclosed in U.S. Pat. No. 6,310,237; the “virus-directed enzyme prodrug therapy (VDEPT)” was published in Proc. Natl. Acad. Sci. USA (1991) 88, 8039; and the “cell ablation therapy” was published in Endocrine Related Cancer, 1997, 4, 67-74.
Since nitroaromatic compounds could be reduced by a flavin-protease existed in mammalian and in bacteria to achieve gradual addition of up to six electrons, while a major enzymatically metabolized product is typically a four-electrons-containing adduct (hydroxylamine), so the nitroaromatic compound may serve as a prodrug in the various therapies mentioned above.
Knox, et al. [Cancer Med Rev., 1993, 12, 195] and Friedlos, et al. [J. Met. Chem., 1997, 40, 1270] reports that dinitrobenzamide ethyleneimine and nitro or dinitrobenzamide nitrogen mustards serve as a substrate for a nitroreductase (NTR) of the aerobic Escherichia coli, and also serve as a specific prodrug in combination with the NTR's GDEPT.
CN200380102812.7 discloses a cytotoxic and nitroaniline-based asymmetric nitrogen mustard as a prodrug, which is usable as a nitroreductase, especially the nitroreductase encoded by E. coli nsfB gene or by Clostridium species in the GDEPT and cell ablation therapy.
However, there is still a need for developing a novel nitroaromatic compound for treating tumors, which is capable of acting as a prodrug in the above therapies.